1. Field of the Invention
The present disclosure in general relates to a method for treating synaptopathy. More particularly, the present disclosure relates to a method for ameliorating the symptom associated with synaptopathy caused by impairment in neurofibromin (NF1 protein), valosin-containing protein (VCP), atlastin-1 (ATL1), or superoxide dismutase 1 (SOD1).
2. Description of Related Art
A dendritic spine is a small membranous protrusion from a neuron's dendrite that typically receives input from a single synapse of an axon. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical signals to the neuron's cell body. Most spines have a bulbous head (the spine head), and a thin neck that connects the head of the spine to the shaft of the dendrite. Spines are very plastic; that is, spines change significantly in shape, volume, and number in small time courses responding to various stimuli. The spine plasticity plays a critical role in perception, cognition, and motivation of a subject. It is known that the impairment in spine morphology and density would affect the motivation or cognitive performance (e.g., learning disability, attention deficit, memory impairment, behavioral difficulty, intellectual disability, impairment in social interaction, or a combination thereof).
Neurofibromin (NF1 protein), encoded by NF1 gene, is a negative regulator of Ras signal transduction pathway and a modulator of adenylyl cyclase pathway. Based on the regulatory role in cell growth and metabolism, mutations in the NF1 gene are associated with various diseases, including tumors (e.g., breast cancer, retinoblastoma, and leukemia), Watson syndrome, and neurofibromatosis type I. Neurofibromatosis type I, a common autosomal dominant disorder, has an incidence of 1 in 3000-4000, half of which are de novo cases. The disease is characterized by progressive neurocutaneous manifestations, including café au lait macules (CALMs), axillary freckling, neurofibromas, and Lisch nodules. Neurofibromatosis type I in children is also frequently associated with cognitive impairments, which are characterized by problems with visuospatial skills, memory, language, executive functioning, and attention. Because of these problems, up to 50-60% and 30-40% of children with Neurofibromatosis type I suffer from learning disabilities and associate with autism spectrum disorders, respectively. Most NF1 children and autism patients need additional support in the form of special education or remedial teaching.
Valosin-containing protein (VCP), encoded by VCP gene and also known as transitional endoplasmic reticulum ATPase (TER ATPase), is a multifunctional AAA (ATPase associated with a variety of cellular activities) protein that functions as a chaperon to control diverse cellular processes. Besides, VCP also functions as an ubiquitin segregase that remodels multimeric protein complexes by extracting polyubiquininated proteins for recycling or promoting degradation by the proteasome. For the implication in widely cellular event, mutations in VCP gene are causative of a pleiotropic degenerative disorder called multisystem proteinopathy (MSP) that can affect muscle, bone and/or the central nervous system. Further, MSP can manifest clinically as frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), autism spectrum disorders (ASDs), inclusion body myopathy (IBM), Paget's disease of bone (PDB), or as a combination of these disorders. Patients suffering from FTD, ALS and ASD usually present with different degrees of cognitive symptoms, such as deficits in social and personal behavior, blunting of emotions, deficits in both expressive and receptive language, and cognitive delays. As of today, few effective treatments are available, most of which merely alleviate the associated symptoms. Accordingly, both patients and their families face the emotional challenges of dealing with the disability and looking ahead to further deterioration.
Superoxide dismutase (also known as superoxide dismutase 1 or SOD1) is an enzyme encoded by SOD1 gene. SOD1 binds copper and zinc ion and is responsible for destroying free superoxide radicals in the body. It is reported that mutations in SOD1 can cause familial amyotrophic lateral sclerosis (ALS), a motor neuron disease that involves the death of neurons and is characterized by stiff muscles, muscle twitching and gradually worsening weakness. The disease usually starts around the age of 60 and in inherited cases around the age of 50. The average survival from onset to death is three to four years, and most die from respiratory failure. To date, there is no effective treatment for ALS.
Atlastin (also known as Atlastin-1), a protein encoded by ATL1 gene, is a dynamin-related GTPase, which plays a role in formation of the tubular endoplasmic reticulum (ER) network and in axon elongation in neurons. It is reported that a heterozygous mutation in ATL1 gene is associated with hereditary spastic paraplegia (HSP), a disease characterized by lower limb spasticity and weakness. Further, HSP is classified as complex or complicated when associated with other neurological signs, including severe amyotrophy, mental retardation, dementia, extrapyramidal signs, deafness or epilepsy, or with extraneurological signs. Nowadays, no specific treatment is known that would prevent, slow, or reverse HSP.
In view of the forging, there exists in the related art a need for an effective method of treating the synaptopathy caused by impairment in NF1, VCP, ATL1, or SOD1 so as to improving the quality of life for patients and their families.